Implicated in over one of every six deaths, cigarette smoking is the leading preventable cause of death in the United States. See, U.S.D.H.H.S., "The Health Benefits of Smoking Cessation", A Report of the Surgeon General. Rockville. Md.: Public Health Service (1990). Unfortunately, nearly 50 million Americans continue to smoke. See, "Cigarette Smoking Among Adults--United States", Centers for Disease Control and Prevention, (1992), and "Changes in Definition of Smoking", JAMA, Vol. 272, pp. 14-16 (1994). With currently available treatment, long-term smoking abstinence rates are generally less than 30%. See, Fiore, Smith, and Baker, "The Effectiveness of the Nicotine Patch in Smoking Cessation", JAMA, Vol. 271, pp. 1940-1947 (1994).
With the increasing recognition of the health hazards associated with the smoking of tobacco, particularly cigarette smoking, increasing attention has been focused on less harmful means to provide some of the satisfaction obtained by smoking. By temporarily giving the smoker an alternative source of nicotine, smoking withdrawal symptoms can be relieved and smoking abstinence facilitated. Some of the alternative sources rely on nicotine replacement through nicotine chewing gum, nicotine skin patches, nicotine nasal sprays, or nicotine vapor inhalers. See, Rose, J. E., "Nicotine Addiction and Treatment", Ann. Rev. Med., Vol. 47, pp. 493-507 (1996). Also, buccal administration of a nicotine lozenge that has an alkaline pH is shown in U.S. Pat. No. 5,549,906 issued Aug. 27, 1996 to Santus.
In addition to smoking cessation, alternative forms of nicotine administration may have applicability in long-term maintenance, to reduce, if not entirely to eliminate, the harm resulting from smoking related diseases, which diseases, have been suggested by epidemiologic and basic biological research, to result from non-nicotine constituents in smoke. Not only does the "tar" fraction of tobacco smoke contains numerous potent carcinogens including nitrosamines and polynuclear aromatic hydrocarbons, but also other toxic fractions of tobacco smoke include carbon monoxide, hydrogen cyanide, and acrolein. See, Hoffman, D. and Hoffman, I., "The Changing Cigarette", J. Toxicol. Environ. Health, Vol. 50, pp. 307-364 (1997).
In contrast, little evidence exists to implicate nicotine in smoking related diseases. Epidemiologic evidence from studies of smokeless tobacco users and pipe and cigar smokers, who obtain substantial levels of nicotine but do not inhale significant quantities of smoke, show little increased morbidity and mortality, with the exception of cancer that probably results from non-nicotine tobacco constituents. See, Wald, N. J. and Waft, H. C., "Prospective Study of Effect of Switching from Cigarettes to Pipes or Cigars on Mortality from Three Smoking Related Diseases", Br. Med. J., Vol. 314, pp. 1860-1863 (1997).
Aside from application in smoking cessation treatment, there is increasing evidence that nicotine may provide therapeutic benefits in the treatment of ulcerative colitis, and in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. See, Westman, E. C., Levin, E. D., and Rose, J. E., "Nicotine as a Therapeutic Drug", N.C. Med. J., Vol. 56, pp. 48-51 (1995), which shows intravenous administration of nicotine to treat ulcerative colitis. More studies vis-a-vis nicotine to treat ulcerative colitis are reported in Zins, Sandborn, Mays, Lawson, McKinney, Tremainc, Mahoney, Zinsmeister, Hurt, Offord, and Lipsky, "Pharmacokinetics of Nicotine Tartrate after Single-Dose Liquid Enema, Oral, and Intravenous Administration", J.Clin. Pharmacol., Vol. 37, pp. 426-436 (May, 1997), which shows a nicotine solution (see, p. 428) that was drunk by the subjects to effect 45 .mu.g of nicotine per kg of body weight, as well as a nicotine capsule that was swallowed by the subjects.
However, nicotine that is swallowed is absorbed from the small intestine and must pass through the liver prior to entering the general circulation. See, Benowitz, N. L., Porchet, H., and Jacob, P. I., "Pharmacokinetics, Metabolism, and Pharmacodynamics of Nicotine", Wonnacott, S., Russell, M. A. H., and Stolerman, I. P. (Eds.), Nicotine Psychopharmacology (pp. 112-157), Oxford: Oxford University Press (1990). Because the liver metabolizes much of the nicotine during this first pass absorption, it has generally been thought that nicotine swallowed by drinking a solution would not be an effective way to administer nicotine as an aid to smokers in their attempts to cease the smoking of tobacco since large doses of nicotine would have to be given to bypass the portal vein entry of the liver, and as is well known, nicotine has an aversive bitter, burning taste. This limits the acceptability of drinking a liquid solution of nicotine. The smokers would not drink nicotine because they would not like the taste of nicotine in a large enough amount when drunk in order to obviate the problem of the first pass absorption by the liver.
Moreover, although Jarvik, M. E., Glick, S. D., and Nakamura, R. K., "Inhibition of Cigarette Smoking by Orally Administered Nicotine", Clin. Pharmacol. Ther., Vol. 11, pp. 574-576 (1970) showed that nicotine administered in capsules produced effects on smoking behavior presumably resulting from some nicotine absorption, and Benowitz, N. L., Jacob, P., Denaro, C., and Jenkins, R., "Stable Isotope Studies of Nicotine Kinetics and Bioavailability", Clin. Pharmacol. Ther., Vol. 49, pp. 270-277 (1991) reported systemic levels similar to those produced by chewing nicotine gum after subjects swallowed capsules containing nicotine, it has nonetheless been felt that the large doses of nicotine needed to overcome first-pass liver metabolic effects would produce intolerable gastrointestinal irritation. Indeed, one of the subjects in the above-noted Benowitz et al. study entitled "Pharmacokinetics, Metabolism, and Pharmacodynamics of Nicotine" complained of nausea and abdominal cramping after a capsule containing nicotine was swallowed.
Thus, since each of the current nicotine replacement products, while having a role in smoking cessation and perhaps also in long-term maintenance, has significant drawbacks, there is a need for conveniently dispensed and well-tolerated nicotine formulations instead of cigarette smoking. For example, for many smokers nicotine chewing gum not only has an unappealing taste resulting from the local high concentration of nicotine in the mouth, but also is difficult to chew. See, Rose, J. E., "Nicotine Addiction and Treatment", Ann. Rev. Med., Vol. 47, pp. 493-507 (1996). Nicotine patches do not provide rapid absorption of nicotine which some smokers prefer, can produce skin irritation in some individuals, and lack the desired sensory and ritual aspects of oral smoking behavior. See, Westman, E. C., Behm F. M., and Rose, J. E., "Airway Sensory Replacement as a Treatment for Smoking Cessation", Vol. 38, pp. 257-262 (1996). Nicotine nasal spray is often perceived as irritating, initially producing aversive reactions of sneezing and tearing. See, Sutherland, G., Stapleton, J. A., Russell, M. A. H., Jarvis, M. J., Hajek, P., Belcher, M., and Feyerabend, C., "Randomised Controlled Trial of Nasal Nicotine Spray in Smoking Cessation", Lancet, Vol. 340, pp. 324-329 (1992). Finally, the nicotine vapor inhaler can produce mouth and throat irritation, delivers low doses of nicotine often inadequate to satisfy many smokers, and some smokers view the puffing behavior as too similar to smoking tobacco as they are attempting to quit. See, Schneider, et al., "Efficacy of a Nicotine Inhaler in Smoking Cessation: A Double-Blind, Placebo-Controlled Trial", Addiction, Vol. 91, pp. 1293-1306 (1996). Thus, a continuing need exists for nicotine replacement products that are acceptable in terms of sensory aspects and yet provide an easily regulated nicotine dose that has an acceptable taste and can be self-administered.